The present invention is concerned with novel compounds of formula (I) having superior gastrokinetic properties. The invention further relates to methods for preparing such novel compounds, pharmaceutical compositions comprising said novel compounds as well as the use as a medicine of said compounds.
Compounds structurally related to the present novel compounds are disclosed in the prior art. WO 93/05038, published on Mar. 18, 1993, discloses (1-butyl-4-piperidinyl)methyl 8-amino-7-chloro-1,4-benzodioxan-5-carboxylate having 5 HT4 receptor antagonistic activity. WO 93/16072, published on Aug. 19, 1993 discloses (1-butyl-4-piperidinyl)methyl-5-amino-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxylate hydrochloride having 5 HT4 receptor antagonistic activity. Recently, Fancelli D. et al., Bioorganic and Medicinal Chem. Lett., 6:263-266, 1996, and WO-96/33186, published on Oct. 24, 1996, disclose (1-butyl-4-piperidinyl)methyl-4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylate hydrochloride having 5 HT4 receptor agonistic activity.
WO 94/29298, published on Dec. 22, 1994 discloses 8-amino-7-chloro-1,4-benzodioxan-5-(1-butyl-4-piperidinyl)carboxylate having 5 HT4 receptor antagonistic activity. WO 94/10174, published on May 11, 1994 discloses 5-(1-(3-pyridylmethyl)-4-piperidinyl)methyl-8-amino-7-chloro-1,4-benzo-dioxancarboxylate, [1-(2-carbo-ethoxyethyl)-4-piperidinyl]methyl-8-amino-7-chloro-1,4-benzodioxan-5-carboxylate, [1-(3-hydroxybutyl)-4-piperidinyl]methyl-8-amino-7-chloro-1,4-benzodioxan-5-carboxylate having 5 HT4 receptor antagonistic activity. Also, WO-96/28424, published on Sep. 19, 1996, discloses disubstituted 1,4-piperidine esters and amides having 5 HT4 receptor antagonistic activity.
The cited prior art documents disclose compounds having 5 HT4 receptor antagonistic activity and may generally be used in the treatment or prophylaxis of gastrointestinal disorders, cardiovascular disorders and CNS disorders. In particular, these compounds are thought to be useful in the treatment of irritable bowel syndrome (IBS), especially the diarrhoea aspects of IBS by blocking the ability of 5-HT to stimulate gut motility.
The problem which this invention sets out to solve is to provide gastric prokinetic compounds, i.e. the actual stimulation of gastric motility.
It is generally believed that gastric prokinetic activity is correlated with 5 HT4 receptor agonist activity, i.e. the opposite of 5 HT4 antagonist activity, (King F. D. et al., J. Med. Chem., 36:683-689, 1993 and Langlois M. et al., Bioorganic and Medicinal Chem. Lett., 4:1433-1436, 1994).
Hence it was surprising to find that the present compounds of formula (I) show gastric prokinetic activity.
In one embodiment, this invention concerns the use of compounds of formula 
the N-oxide forms, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein
R1 is C1-6alkyloxy, C2-6alkenyloxy or C2-6alkynyloxy;
R2 is hydrogen or C1-6alkyloxy,
or when taken together R1 and R2 may form a bivalent radical of formula
xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(a-1),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(a-2),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(a-3),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(a-4),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(a-5),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(a-6),
xe2x80x83wherein in said bivalent radicals one or two hydrogen atoms may be substituted with C1-6alkyl;
R3 is hydrogen or halo;
L is C3-6cycloalkyl, C5-6cycloalkanone, C2-6alkenyl optionally substituted with Ar, or L is a radical of formula 
xe2x80x83wherein
Alk is C1-12alkanediyl;
R4 is hydrogen, C1-6alkylsulfonylamino, C3-6cycloalkyl, C5-6cycloalkanone, Ar-, di(Ar)methyl, Ar-oxy- or Het1;
R5 is hydrogen or C1-6alkyl;
R6 is Het2;
R7 is hydrogen, C1-6alkyl, hydroxyC1-6alkyl, C3-6cycloalkyl, Ar or Het2;
X is O, S, SO2 or NR8; said R8 being hydrogen, C1-6alkyl or Ar,
R9 is hydrogen, C1-6alkyl, C3-6cycloalkyl, Ar, ArC1-6alkyl, di(Ar)methyl, C1-6alkyloxy or hydroxy;
Y is NR10 or a direct bond; said R10 being hydrogen, C1-6alkyl or Ar;
R11 and R12 each independently are hydrogen, C1-6alkyl, C3-6cycloalkyl, Ar or ArC1-6alkyl, or R11 and R12 combined with the nitrogen atom bearing R11 and R12 may form a pyrrolidinyl or piperidinyl ring both being optionally substituted with C1-6alkyl, amino or mono or di(C1-6alkyl)amino, or said R11 and R12 combined with the nitrogen bearing R11 and R12 may form a piperazinyl or 4-morpholinyl radical both being optionally substituted with C1-6alkyl;
each Ar being unsubstituted phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, hydroxy, C1-6alkyl, C1-6alkyloxy, aminosulfonyl, C1-6alkylcarbonyl, nitro, trifluoromethyl, amino or aminocarbonyl; and
Het1 and Het2 each independently are selected from furan; furan substituted with C1-6alkyl or halo; tetrahydrofuran; a tetrahydrofuran substituted with C1-6alkyl; a dioxolane; a dioxolane substituted with C1-6alkyl, a dioxane; a dioxane substituted with C1-6alkyl; tetrahydropyran; a tetrahydropyran substituted with C1-6alkyl; pyrrolidinyl; pyrrolidinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, or C1-6alkyl; pyridinyl; pyridinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, C1-6alkyl; pyrimidinyl; pyrimidinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, C1-6alkyl, C1-6alkyloxy, amino and mono and di(C1-6alkyl)amino; pyridazinyl; pyridazinyl substituted with one or two substituents each independently selected from hydroxy, C1-6alkyloxy, C1-6alkyl or halo; pyrazinyl; pyrazinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, C1-6alkyl, C1-6alkyloxy, amino, mono- and di(C1-6alkyl)amino and C1-6alkyloxycarbonyl;
Het1 can also be a radical of formula 
Het1 and Het2 each independently can also be selected from the radicals of formula 
R13 and R14 each independently are hydrogen or C1-4alkyl;
with the proviso that L is other than n-butyl when R1 and R2 are taken together to form a bivalent radical of formula (a-2);
for the manufacture of a medicine for treating conditions involving a decreased motility of the stomach.
In another embodiment, this invention concerns novel compounds of formula (Ixe2x80x2) 
the N-oxide forms, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein
R1 is C1-6alkyloxy, C2-6alkenyloxy or C2-6alkynyloxy;
R2 is hydrogen or C1-6alkyloxy,
or when taken together R1 and R2 may form a bivalent radical of formula
xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(a-1),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(a-2),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(a-3),
xe2x80x83xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(a-4),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(a-5),
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(a-6),
xe2x80x83wherein in said bivalent radicals one or two hydrogen atoms may be substituted with C1-6alkyl;
R3 is hydrogen or halo;
L is C3-6cycloalkyl, C5-6cycloalkanone, C2-6alkenyl optionally substituted with Ar, or L is a radical of formula 
xe2x80x83wherein
Alk is C1-12alkanediyl;
R4 is hydrogen, C1-6alkylsulfonylamino, C3-6cycloalkyl, C5-6cycloalkanone, Ar-, di(Ar)methyl, Ar-oxy- or Het1;
R5 is hydrogen or C1-6alkyl;
R6 is Het2;
R7 is hydrogen, C1-6alkyl, hydroxyC1-6alkyl, C3-6cycloalkyl, Ar or Het2;
X is O, S, SO2 or NR8; said R8 being hydrogen, C1-6alkyl or Ar;
R9 is hydrogen, C1-6alkyl, C3-6cycloalkyl, Ar, ArC1-6alkyl, di(Ar)methyl, C1-6alkyloxy or hydroxy;
Y is NR10 or a direct bond; said R10 being hydrogen, C1-6alkyl or Ar;
R11 and R12 each independently are hydrogen, C1-6alkyl, C3-6cycloalkyl, Ar or ArC1-6alkyl, or R11 and R12 combined with the nitrogen atom bearing R11 and R12 may form a pyrrolidinyl or piperidinyl ring both being optionally substituted with C1-6alkyl, amino or mono or di(C1-6alkyl)amino, or said R11 and R12 combined with the nitrogen bearing R11 and R12 may form a piperazinyl or 4-morpholinyl radical both being optionally substituted with C1-6alkyl;
each Ar being unsubstituted phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, hydroxy, C1-6alkyl, C1-6alkyloxy, aminosulfonyl, C1-6alkylcarbonyl, nitro, trifluoromethyl, amino or aminocarbonyl; and
Het1 and Het2 each independently are selected from furan; furan substituted with C1-6alkyl or halo; tetrahydrofuran; a tetrahydrofuran substituted with C1-6alkyl; a dioxolane; a dioxolane substituted with C1-6alkyl, a dioxane; a dioxane substituted with C1-6alkyl; tetrahydropyran; a tetrahydropyran substituted with C1-6alkyl; pyrrolidinyl; pyrrolidinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, or C1-6alkyl; pyridinyl; pyridinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, C1-6alkyl; pyrimidinyl; pyrimidinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, C1-6alkyl, C1-6alkyloxy, amino and mono and di(C1-6alkyl)amino; pyridazinyl; pyridazinyl substituted with one or two substituents each independently selected from hydroxy, C1-6alkyloxy, C1-6alkyl or halo; pyrazinyl; pyrazinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, C1-6alkyl, C1-6alkyloxy, amino, mono- and di(C1-6alkyl)amino and C1-6alkyloxycarbonyl;
Het1 can also be a radical of formula 
Het1 and Het2 each independently can also be selected from the radicals of formula 
R13 and R14 each independently are hydrogen or C1-4alkyl;
with the proviso that R4 is other than hydrogen, phenyl, 4-fluorophenyl, 4-methylphenyl or 4-methoxyphenyl when R1 and R2 are taken together to form a bivalent radical of formula xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94; or L is other than n-butyl when R1 and R2 are taken together to form a bivalent radical of formula (a-2) or (a4).
The proviso is intended to exclude compounds E1, E2, E22-E25, E27, E28, E30, E39-E42 which are disclosed in WO-93/05038, compound E6 disclosed in WO-93/16072 and compound FCE 29029A disclosed in WO-96/33186.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C1-4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl and the like; C1-6alkyl is meant to include C1-4alkyl and the higher homologues thereof having 5 or 6 carbon atoms, such as, for example, 2-methylbutyl, pentyl, hexyl and the like; C2-6alkenyl defines straight and branched chain unsaturated hydrocarbon radicals having from 2 to 6 carbon atoms, such as ethenyl, propenyl, butenyl, pentenyl or hexenyl; C2-6alkynyl defines straight and branched chain hydrocarbon radicals having from 2 to 6 atoms containing a triple bond, such as ethynyl, propynyl, butynyl, pentynyl or hexynyl; C1-5alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 5 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl and the like; and C1-6alkanediyl is meant to include C1-5alkanediyl and the higher homologues thereof having 6 carbon atoms, such as, for example, 1,6-hexanediyl and the like.
The term xe2x80x9cstereochemically isomeric formsxe2x80x9d as used hereinbefore defines all the possible isomeric forms which the compounds of formula (I) or (Ixe2x80x2) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the R- or S-configuration. Stereochemically isomeric forms of the compounds of formula (I) or (Ixe2x80x2) are obviously intended to be embraced within the scope of this invention.
Some of the compounds of formula (I) or (Ixe2x80x2) may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. For instance, compounds of formula (I) or (Ixe2x80x2) wherein Het1 or Het2 is pyrimidinyl substituted with hydroxy, may exist in their corresponding tautomeric form.
The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) or (Ixe2x80x2) are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.
The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) or (Ixe2x80x2) as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.
The N-oxide forms of the compounds of formula (I) or (Ixe2x80x2) are meant to comprise those compounds of formula (I) or (Ixe2x80x2) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide, particularly those N-oxides wherein the piperidine-nitrogen is N-oxidized.
Whenever used hereinafter, the term xe2x80x9ccompounds of formula (I) or (Ixe2x80x2)xe2x80x9d is meant to also include their N-oxide forms, their pharmaceutically acceptable addition salts, and their stereochemically isomeric forms.
A first interesting group of compounds consists of compounds of formula (Ixe2x80x2) wherein R1 and R2 are taken together to form a radical of formula (a-2) or (a-3), wherein optionally one or two hydrogen atoms are substituted with methyl; and R3 is halo.
A second group of interesting compounds are those compounds of formula (Ixe2x80x2) wherein R1 is methoxy, R2 is hydrogen and R3 is chloro.
A particular group of compounds are those compounds of formula (Ixe2x80x2) wherein L is a radical of formula (b-1) and R4 is Het1 or substituted phenyloxy.
Another particular group of compounds are those compounds formula (Ixe2x80x2) wherein L is a radical of formula (b-2) or (b-3) and R6 is Het2.
Preferred compounds are those wherein R1 and R2 are taken together to form a radical of formula (a-2) or (a-3), wherein optionally one or two hydrogen atoms are substituted with methyl; R3 is chloro; L is a radical of formula (b-1), (b-2) or (b-3) wherein R4 is substituted phenyloxy, R5 is hydrogen and R6 is Het2; in particular R4 is phenyloxy substituted with halo and R6 is pyrazidinyl or imidazolyl optionally substituted with hydroxy or C1-6alkyl.
Most preferred are [1-[2-[(3-methyl-2-pyrazinyl)amino]ethyl]-4-piperidinyl]methyl 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate; or [1-[2-[2,3-dihydro-3-(1-methylethyl)-2-oxo-1H-imidazol-1-yl]ethyl]-4-piperidinyl]-methyl 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate; or [1-[2-[(3-methyl-2-pyrazinyl)amino]ethyl]-4-piperidinyl]methyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylate; or [1-[1-(3-methyl-2-pyrazinyl)-4-piperidinyl]-4-piperidinyl]methyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylate; and the pharmaceutically acceptable acid addition salts and the stereo isomeric forms thereof.
The compounds of formula (Ixe2x80x2) may generally be prepared by reacting an intermediate of formula (II) with a carboxylic acid derivative of formula (II) or a reactive functional derivative thereof, such as, for example, an acid chloride or a carbonyl imidazole derivative. Said esterbond formation may be performed by stirring the reactants in an appropriate solvent in the presence of a base, such as sodium imidazolide. 
Another way of preparing compounds of formula (Ixe2x80x2) is by N-alkylating an intermediate of formula (V) with an intermediate of formula (IV), wherein W is an appropriate leaving group such as, for example, a halogen, e.g. chloro or bromo, or a sulfonyloxy leaving group, erg. methanesulfonyloxy or benzenesulfonyloxy. 
Said N-alkylation reaction can be performed in a reaction-inert solvent such as, for example, a dipolar aprotic solvent, e.g. N,N-dimethylformamide, or a ketone, e.g. methyl isobutylketone, and in the presence of a suitable base such as, for example, sodium carbonate, sodium hydrogen carbonate or triethylamine. Stirring may enhance the rate of the reaction. The reaction may conveniently be carried out at a temperature ranging between room temperature and reflux temperature.
Alternatively, an intermediate of formula (V) is reductively N-alkylated with an intermediate of formula Lxe2x80x2xe2x95x90O (IV-a), wherein Lxe2x80x2xe2x95x90O represents a derivative of formula Lxe2x80x94H wherein two geminal hydrogen atoms are replaced by oxygen, following xe2x80x9cart-known reductive N-alkylation proceduresxe2x80x9d. 
Said reductive N-alkylation may be performed in a reaction-inert solvent such as, for example, dichloromethane, ethanol, toluene or a mixture thereof, and in the presence of a reducing agent such as, for example, a borohydride, e.g. sodium borohydride, sodium cyanoborohydride or triacetoxy borohydride. It may also be convenient to use hydrogen as a reducing agent in combination with a suitable catalyst such as, for example, palladium-on-charcoal or platinum-on-charcoal. In case hydrogen is used as reducing agent, it may be advantageous to add a dehydrating agent to the reaction mixture such as, for example, aluminium tert-butoxide. In order to prevent the undesired further hydrogenation of certain functional groups in the reactants and the reaction products, it may also be advantageous to add an appropriate catalyst-poison to the reaction mixture, e.g., thiophene or quinoline-sulphur. To enhance the rate of the reaction, the temperature may be elevated in a range between room temperature and the reflux temperature of the reaction mixture and optionally the pressure of the hydrogen gas may be raised.
Further, compounds of formula (Ixe2x80x2) wherein L is Alkxe2x80x2-NHR6 and Alkxe2x80x2 is C2-6alkanediyl, said compounds being represented by formula (Ixe2x80x2-a), can be prepared by treating intermediates (VII) with intermediates (VI), wherein W1 is a suitable leaving group such as, a halo, e.g. chloro, bromo or iodo, or an alkylthio, e.g. methylthio, in an appropriate solvent e.g. acetonitrile or dimethylacetamide. 
Also, compounds of formula (Ixe2x80x2) may be prepared by carbonylation of an intermediate of formula (XII), wherein X is bromo or iodo, in the presence of an intermediate of formula (II). 
Said carbonylation reaction is carried out in a reaction-inert solvent such as, e.g. acetonitrile or tetrahydrofuran, in the presence of a suitable catalyst and a tertiary amine such as, e.g. triethylamine, and at a temperature ranging between room temperature and the reflux temperature of the reaction mixture. Suitable catalysts are, for instance, palladium-on-carbon, palladium(triphenylphosphine) complexes or Raney nickel. Carbon monoxide is administered at atmospheric pressure or at an increased pressure. Analogous carbonylation reactions are described in Chapter 8 of xe2x80x9cPalladium reagents in organic synthesesxe2x80x9d, Academic Press Ltd., Benchtop Edition 1990, by Richard F. Heck; and the references cited therein.
The compounds of formula (I) may further be prepared by converting compounds of formula (I) into each other according to art-known group transformation reactions.
The compounds of formula (I) may also be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
The starting materials and some of the intermediates are known compounds and are commercially available or may be prepared according to conventional reaction procedures generally known in the art. For instance, some intermediates of formula (III) have been described in EP-0,389,037.
An intermediate of formula (V) may be prepared by reacting an intermediate of formula (VIII), wherein PG represents an appropriate protective group, such as, for example, a tert-butoxycarbonyl, a benzyl group or a photoremovable group, with an acid of formula (III) or an appropriate reactive functional derivative thereof, and subsequent deprotection of the thus formed intermediate, i.e. removal of PG by art-known methods. 
An intermediate of formula (II) may be prepared by reacting an intermediate of formula (IX), which may be prepared by deprotecting an intermediate of formula (VIII), with an intermediate of formula (IV). 
In some cases, it may be appropriate to protect the primary alcohol functionality during the reactionsequence starting from intermediate (IX) to intermediate (II). Protecting groups for primary alcohol functionalities are art-known. These protecting groups may then be removed at the appropriate time during the further synthesis.
Intermediates of formula (VII) can be prepared by treating an intermediate (V) with an intermediate of formula (X), wherein W2 is an appropriate leaving group such as, for example, a halogen, e.g. chloro or bromo, or a sulfonyloxy leaving group, e.g. methane-sulfonyloxy or benzenesulfonyloxy, and Alkxe2x80x3 is C1-5alkanediyl, according to the previously described N-alkylation method, and subsequent reduction of intermediate (XI) with an appropriate reducing agent such as, e.g. Raney nickel, in a reaction-inert solvent e.g. THF and in the presence of hydrogen. 
Ester derivatives of intermediates of formula (III) can generally be prepared by carbonylating an intermediate of formula (XII), wherein X is bromo or iodo in the presence of an alcohol of formula (XIV), wherein R is C1-6alkyl. 
Said carbonylation reaction is carried out in a reaction-inert solvent such as, e.g. acetonitrile or tetrahydrofuran, in the presence of a suitable catalyst and potassium acetate or a tertiary amine such as, e.g. triethylamine, and at a temperature ranging between room temperature and the reflux temperature of the reaction mixture. Suitable catalysts are, for instance, palladium-on-carbon or Raney nickel. Carbon monoxide is administered at atmospheric pressure or at an increased pressure. Analogous carbonylation reactions are described in Chapter 8 of xe2x80x9cPalladium reagents in organic synthesesxe2x80x9d, Academic Press Ltd., Benchtop Edition 1990, by Richard F. Heck; and the references cited therein.
The compounds of formula (I) as prepared in the hereinabove described processes may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
The compounds of formula (I) or (Ixe2x80x2), the N-oxide forms, the pharmaceutically acceptable salts and stereoisomeric forms thereof possess favourable intestinal motility stimulating properties. In particular the present compounds show significant gastric emptying activity as is evidenced in example C.1, the xe2x80x9cGastric emptying of an acaloric liquid meal delayed by administration of lidamidine in conscious dogsxe2x80x9d-test.
In view of the capability of the compounds of the present invention to enhance the gastrointestinal motility, and in particular to activate gastric emptying, the subject compounds are useful to treat conditions related to a hampered or impaired gastric emptying and more generally to treat conditions related to a hampered or impaired gastrointestinal transit.
The compounds of formula (I) also are believed to have a beneficial effect on the pressure of the LES (Lower Esophagus Sphincter).
Some of the compounds of the present invention also have colon motility stimulating properties.
In view of the utility of the compounds of formula (I), it follows that the present invention also provides a method of treating warm-blooded animals, including humans, (generally called herein patients) suffering from conditions related to a hampered or impaired gastric emptying or more generally suffering from conditions related to a hampered or impaired gastrointestinal transit. Consequently a method of treatment is provided for relieving patients suffering from conditions, such as, for example, gastro-oesophageal reflux, dyspepsia, gastroparesis, constipation, post-operative ileus, and intestinal pseudo-obstruction. Gastroparesis can be brought about by an abnormality in the stomach or as a complication of diseases such as diabetes, progressive systemic sclerosis, anorexia nervosa and myotonic dystrophy. Constipation can result form conditions such as lack of intestinal muscle tone or intestinal spasticity. Post-operative ileus is an obstruction or a kinetic impairment in the intestine due to a disruption in muscle tone following surgery. Intestinal pseudo-obstruction is a condition characterized by constipation, colicky pain, and vomiting, but without evidence of physical obstruction. The compounds of the present invention can thus be used either to take away the actual cause of the condition or to relief the patients from symptoms of the conditions. Dyspepsia is an impairment of the function of digestion, that can arise as a symptom of a primary gastrointestinal dysfunction, especially a gastrointestinal dysfunction related to an increased muscle tone or as a complication due to other disorders such as appendicitis, gallbladder disturbances, or malnutrition.
The symptoms of dyspepsia may also arise due to the intake of chemical substances, e.g. SSRI""s.
Hence, the use of a compound of formula (Ixe2x80x2) as medicine is provided, and in particular the use of a compound of formula (I) for the manufacture of a medicine for treating conditions involving a decreased motility of the stomach. Both prophylactic and therapeutic treatment are envisaged.
To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant deleterious effect to the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment. Acid addition salts of (I) due to their increased water solubility over the corresponding base form, are obviously more suitable in the preparation of aqueous compositions.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
In general it is contemplated that a therapeutically effective amount would be from about 0.001 mg/kg to about 10 mg/kg body weight, preferably from about 0.02 mg/kg to about 5 mg/kg body weight. A method of treatment may also include administering the active ingredient on a regimen of between one to four intakes per day.